Glutamate receptor modulators and therapeutic agents

ABSTRACT

The present invention discloses methods of modulating the activity of Group I mGluRs using a defined class of benzamide compounds. In one embodiment, methods of modulating the activity of mGluR1 are provided. In another embodiment, methods of modulating the activity of mGluR5 are provided. In still another embodiment, methods of simultaneously modulating the activities of both mGluR1 and mGluR5 are provided. The present invention also provides methods of treating diseases or disorders which are mediated in full or in part by Group I mGluRs using one or more compounds belonging to the defined class of benzamide compounds. The present invention further provides methods of preventing diseases or disorders which are mediated in full or in part by Group I mGluRs using one or more compounds belonging to the defined class of compounds.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a Divisional of application Ser. No. 12/381,086filed Mar. 6, 2009 now U.S. Pat. No. 8,211,882.

FIELD OF THE INVENTION

The invention relates to compounds and methods to use compounds to treatdiseases or disorders mediated in full or in part by Group 1metabotropic glutamate receptors.

BACKGROUND OF THE INVENTION

The amino acid glutamate (L-glutamic acid) is recognized as the majorexcitatory neurotransmitter in the CNS. The excitatory amino acidreceptors which respond to glutamate are of great physiologicalimportance and play a key role in a variety of physiological processessuch as long-term potentiation (learning and memory), the development ofsynaptic plasticity, motor control, respiratory and cardiovascularregulation, and sensory perception.

Excitatory amino acid receptors are classified into two general typesand both are activated by glutamate and its analogs. Receptors activatedby glutamate that are directly coupled to the opening of cation channelsin the cell membrane of the neurons are termed ionotropic glutamatereceptors (iGluRs). This type of receptor has been subdivided into threesubtypes, which are defined by the depolarizing actions of the selectiveagonists N-Methyl-D-aspartate (NMDA),α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and Kainicacid (KA).

The second general type of glutamate receptor belongs to the G-proteinor second messenger-linked class of receptors and are known as“metabotropic” glutamate receptors (mGluRs). The metabotropic receptorsare coupled to multiple second messenger systems that lead to enhancedphosphoinositide hydrolysis, activation of phospholipase D, increases ordecreases in cyclic adenosine monophosphate (cAMP) formation, andchanges in ion channel function (Schoepp D. et al, 1993; Trends inPharmacological Science 14:13). Both types of receptors appear not onlyto mediate normal synaptic transmission along excitatory pathways butalso to participate in the modification of synaptic connections duringdevelopment and throughout life. Research has shown that mGluRs areimplicated in a number of normal as well as pathological mechanisms inboth the central nervous system and the periphery. Activation ofneuronal mGluRs can influence levels of alertness, attention andcognition, protect nerve cells from excitotoxic damage resulting fromischemia, hypoglycemia and anoxia, modulate the level of neuronalexcitation, influence central mechanisms involved in controllingmovement, reduce sensitivity to pain, and reduce levels of anxiety.

Eight different types of the mGluRs have been identified: mGluR1-8(Knopfel et al., 1995, J. Med. Chem., 38, 1417-1426). These receptorsfunction to modulate the presynaptic release of glutamate, and thepostsynaptic sensitivity of neuronal cells to glutamate excitation.Based on pharmacology, sequence homology, and the signal transductionpathway that they activate, the mGluRs have been sub-classified intothree groups. Group I consists of mGluR1 and mGluR5. They are coupled tohydrolysis of phosphatidylinositol (PI) and are selectively activated by(R,S)-3,5-dihydroxyphenylglycine (Brabet et al. 1995; Neuropharmacology,34, 895-903). Group II consists of mGluR2 and mGluR3 receptors. They arenegatively coupled to adenylate cyclase and are selectively activated by(2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; Hayashi etal. 1993; Nature, 366, 687-690). Group III consists of mGluR4, mGluR6,mGluR7 and mGluR8. They are also negatively coupled to adenylate cyclaseand are selectively activated by (L)-2-amino-4-phosphonobutyric acid(L-AP4).

Antagonists which selectively bind to the mGluRs have been reported.Some phenylglycine derivatives, for example S-4CPG(S-4-carboxyphenylglycine), S-4C3HPG(S-4-carboxy-3-hydroxyphenylglycine) and S-MCPG(S-.alpha.-methyl-4-carboxyphenylglycine) have been reported toantagonize trans-ACPD-stimulated phosphoinositide hydrolysis and thuspossibly act as antagonists at mGluR1 and mGluR5 subtypes (Thomsen, C.et al 1993; Eur. J. Pharmacol. 245:299). More recently, compoundsexhibiting selective agonist or antagonist activity at the mGluRs havebeen reported. Group I receptors (mGluR1 and mGluR5) play a key role inthe central sensitization of pain, in addition to a variety of functionswith potential implications in neurological and psychiatric disorders.(Schoepp, D. et al 1999; Neuropharmacology 38:1431-1476; Han, J. et al2005; Pain 113:211-222.) A number of behavioral and electrophysiologicalstudies have demonstrated a specific role for Group I mGluRs, and inparticular mGluR1 receptors, in nociceptive processing in the CNS,including mechanisms of hyperalgesia and inflammation (Bhave, G. et al2001; Nat. Neurosci. 4:417-423; Dolan, S. et al 2002; Neuropharmacology43:319-326; Dolan, S. et al 2003; Pain 106:501-512; Young, M. et al1994; Neuropharmacology, 33:141-144; Young, M. et al 1997; Brain Res.777:161-169). The mGluR1-active compounds are also implicated in thetreatment of pain. Antagonists at the Group 1 mGluRs antagonize sensorysynaptic response to noxious stimuli of thalamic neurons (Eaton, S. A.et al. 1993; Eur. J. Neuroscience, 5:186). The intrinsic activation ofspinal mGluR1 in chronic nociception has been demonstrated usingantagonists, antibodies, and antisense oligonucleotides. Intrathecaladministration of an mGluR1 antagonist produced antinociceptive effectsin a formalin-induced model of nociceptive behavior (Neugebauer, V.2001; Trends Neurosci. 24:550-552). There is mounting evidence tosuggest that mGluR1 antagonists can be used for the treatment of chronicpain (Neugebauer, V. et al 2002; Expert Opin. Ther. Targets 6:349-361;Swanson, C. et al 2005; Nat. Rev. Drug Discovery 4:131-144). Severalgroups have reported a variety of structurally diverse non-competitiveallosteric mGluR1 antagonists, such as LY456066 (Ambler, S. et atWO2001032632), JNJ16259685 (Mabire, D. et al 2005; J. Med. Chem.,48:2134-2153), A-841720 (Zheng, G. et al 2005; J. Med. Chem.48:7374-7388), and R214127 (Maibre et at WO 02/28837).

The use of compounds active at the mGluRs for the treatment of epilepsywas demonstrated by the influence of trans-ACPD on the formation ofconvulsions (Sacaan et al, Neuroscience Lett. 139, 77, 1992) and thatphosphoinositide hydrolysis mediated via mGluR1 is increased afterconvulsion-causing stimulation experiments in rats (Akiyama et al. BrainRes. 569, 71, 1992). Trans-ACPD has been shown to increase the releaseof dopamine in the rat brain, which indicates that compounds acting onthe mGluRs might be usable for the treatment of Parkinson's disease andHuntington's Chorea disease (Sacaan et al., J. Neurochemistry 59, 245,1992).

Trans-ACPD has also been shown to be a neuroprotective agent in a medialcerebral artery occlusion (MCAO) model in mice (Chiamulera et al. 1992;Eur. J. Pharmacol. 216:335), and it has been shown to inhibitNMDA-induced neurotoxicity in nerve cell cultures (Koh, V. 1991, Proc.Natl. Acad. Sci. USA 88:9431).

Compounds active at the mGluRs for treatment of neurological diseasessuch as senile dementia have also been reported (Zheng, G. et al 1992;Neuron 9:163; Bashir et al 1993; Nature 363:347). These studiesdemonstrated that activation of mGluRs is necessary for the induction oflong-term potentiation (LTP) in nerve cells of the septal nucleus andhippocampus. In addition it was shown that long-term depression (LTD) innerve cells is induced after activation of mGluRs in cerebellar granulecells (Linden et al. 1991; Neuron 7:81). mGluRs may also be involved inaddictive behavior, alcoholism, drug addiction, sensitization and drugwithdrawal (Wickelgren, I. 1998; Science, 280:2045).

In addition to involvement in disorders of the central and peripheralnervous system, mGluRs have recently been implicated as contributing tothe development of certain cancers. In recent years, glutamate signalingin cancer has been a focus of investigation. Studies have implicated theinvolvement of glutamate signaling in tumor development through mGluRs.The role of glutamate signaling in non-neuronal tissues is poorlyunderstood, but studies have shown that a variety of G protein-coupledreceptors and G proteins, including those that signal throughphosphoinositide hydrolysis and cAMP accumulation, have been implicatedin tumorigenesis through either mutational activation or overexpression(Dhanasekaran, N. et al, 1995; Endocr. Rev. 16:259-270; Gutkind, J.1998; Oncogene 17:1331-1342.). Glutamate has recently been linked totumor growth in both neuronal and non-neuronal cancers (Takano, T. etal. 2001; Nat. Med. 7:1010-1015; Rzeski, W. et al 2001; Proc. Natl.Acad. Sci. USA 98:6372-6377). Glutamate has been shown to stimulateproliferation of lung carcinoma cells in serum-deprived media, andantagonists of the ionotropic AMPA and NMDA glutamate receptors havebeen shown to inhibit proliferation and increase cell death in acalcium-dependent manner in a variety of non-neuronal cancers (Rzeski,W. et al 2001; supra). Agonist stimulation of mGluR5 in subconfluentmelanocyte cultures has been shown to result in melanocyticproliferation (Frati, C. et al. 2000; J. Cell. Physiol. 183:364-372). Itwas recently shown that transgenic mice bred to be predisposed todevelop multiple melanomas expressed an abundance of mGluR1 in melanomacells but not in normal melanocytes, and that ectopic expression ofmGluR1 was sufficient to cause melanoma (Pollack, P. et al 2003; NatureGenetics 34:108-112). The same study revealed that mGluR1 expression wasdetected in several human melanoma tumors and cell lines but not inbenign nevi (clusters of melanocytes on the skin) or melanocytes.Several cell lines have been developed from independent mouse melanomatumors (Marin, Y. et al 2005; Neuropharmacol. 49:70-79). These celllines are useful tools in the studies of signaling events that may bemediated by mGluR1 in transformed melanocytes. In these cells,stimulation of mGluR1 by quisqualate, a Group I competitive glutamatereceptor agonist, results in inositol triphosphate (IP3) accumulation,and the activation of the extracellular signal-related protein kinase1/extracellular signal-related protein kinase 2 (ERK1/2) cell signalingpathway. The extracellular signal-regulated kinase (ERK) signalingpathway is a major determinant in the control of diverse cellularprocesses such as proliferation, survival, differentiation and motility.This pathway is often up-regulated in human tumors and as suchrepresents an attractive target for the development of anticancer drugs.Because of its multiple roles in the acquisition of a complex malignantphenotype, specific blockade of the ERK pathway is expected to result innot only an antiproliferative effect but also in antimetastatic andantiangiogenic effects in tumor cells. IP3 accumulation and ERK1/2activation were inhibited by pretreatment of the tumor cells with amGluR1-specific antagonist (S-2-methyl-4-carboxy-phenylglycine,LY367385) or by dominant negative mutants of mGluR1, demonstrating thatstimulation of mGluR1 initiates the ERK pathway but that this action maybe inhibited by an antagonist. It was shown that ERK1/2 activation bymGluR1 was PKC-dependent, but cAMP and PKA-independent. These resultssuggest that mGluR1 and glutamate signaling may be used as novel targetsfor melanoma therapy (Nankoon et al, 2007 Cancer Res. 67:2298-2305).

Several diseases and disorders are mediated by improper functioning ofglutamate receptors. Because excitatory amino acid receptors in generaland mGluRs in particular are implicated in diverse normal physiologicalprocesses, there is a need to identify compounds capable of modulatingreceptor-mediated functions. For example, partial antagonism of mGluRsmight be clinically useful in treating disorders wherein the processmediated by the receptor is pathologically enhanced. Partial antagonismmight be clinically useful in treating disorders wherein the is anoverabundance of the indigenous ligand stimulating the receptor toinduce a critical function. There is a need to identify and developmethods of treatment and methods of prevention of disorders related tothe improper functioning of mGluRs and specifically those in Group I.

BRIEF DESCRIPTION OF THE INVENTION

The present invention discloses methods of modulating the activity ofGroup I mGluRs using a defined class of compounds. Surprisingly, it wasfound that selected benzamide compounds modulated the activity of Group1 mGluRs. In one embodiment, methods of modulating the activity ofmGluR1 are provided. In another embodiment, methods of modulating theactivity of mGluR5 are provided. In still another embodiment, methods ofsimultaneously modulating the activities of both mGluR1 and mGluR5 areprovided. The present invention also provides methods of treatingdiseases or disorders which are mediated in full or in part by Group ImGluRs using one or more compounds belonging to the defined class ofbenzamide compounds. The present invention further provides methods ofpreventing diseases or disorders which are mediated in full or in partby Group I mGluRs using one or more compounds belonging to the definedclass of benzamide compounds. Diseases and disorders contemplatedinclude, but are not limited to, diseases and disorders of the centralnervous system, the peripheral nervous system, the gastrointestinalsystem, the circulatory system, skin, retina, brain, heart, and lungs.It will be clear to those with skill in the art that the distributionand function of Group 1 mGluRs in animals is not completely understood,and that diseases or disorders in which Group 1 mGluRs are implicated,whether known at the present or unveiled in the future, are contemplatedand are within the scope of the instant invention.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 graphically portrays the ability of Compound 1 and Compound 21 toreverse hyperalgesia in the partial sciatic nerve ligation (PSN) modelof neuropathic pain in the rat, as compared to gabapentin.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods of modulating the activity ofGroup I mGluRs, and preventing or treating diseases or disorders whichare mediated by Group I mGluRs, comprising contacting the Group I mGluRswith one or more allosteric modulator of the invention in an amountsufficient to modulate the activity or prevent or treat the disease ordisorder.

Antagonists and agonists of receptors which bind to and are active atonly a particular receptor subtype are “selective” agents, whereas thosewhich bind to and are active at more than one receptor subtype are“non-selective”. “Orthosteric” ligands are agonists or antagonists whichbind to and are active at the primary receptor binding site of areceptor, which is that portion of the receptor to which the endogenousneurotransmitter (glutamate) binds. Orthosteric agents therefore competewith the neurotransmitter for binding at the primary site, and may befurther classified as “competitive” agonists or antagonists. Agonists orantagonists which bind to and are active at a secondary, and in somecases a tertiary, receptor binding site, which are spatially distinctdomains for which the endogenous neurotransmitter has very little or noaffinity, are termed “allosteric” ligands. These allosteric ligands are“non-competitive” in that, even in high concentration, they will notdisplace the endogenous ligand by competing for the primary bindingsite. However, compounds which bind to an allosteric site in a receptormay mitigate, modify, attenuate, enhance, diminish, inhibit, or prohibitthe binding of the endogenous neurotransmitter or other orthostericligand to the primary binding site. Alternatively compounds which bindto an allosteric site in a receptor may mitigate, modify, attenuate,enhance, diminish, inhibit, or prohibit the physiological function ofthe activated receptor which include, among others, ion flux regulation,signaling, phosphorylation, and recruitment of proteins. The potency ofattraction of an agonist or antagonist, whether orthosteric orallosteric, to its binding site in the receptor, is determined by thesum of non-covalent attractive and repulsive chemical forces of theligand for the binding site, and is referred to as “affinity”. A highaffinity agonist or antagonist will bind to its respective site in thereceptor at very low concentration, while much higher concentrations oflow-affinity molecules are required before significant binding occurs.Agonists or antagonists with sufficient affinity to bind to anallosteric site will produce a dramatic change in the physiologicalfunction of an activated mGluR. Such agonists or antagonists arereferred to herein as “allosteric modulators” and may exhibit positive(enhanced physiological function) or negative (diminished physiologicalfunction) modulation. An object of this invention is to provideselective allosteric modulators for the prevention and treatment of adisease or disorder which is associated with abnormal, aberrant, orexcessive function of Group I mGluRs. A further object of this inventionis to provide negative allosteric modulators of mGluR1, negative.allosteric modulators of mGluR5, and negative allosteric modulators ofboth mGluR1 and mGluR5.

According to the present invention, selective allosteric modulators withspecificity for either mGluR1 or mGluR5 are provided. The mGlu1 andmGlu5 receptors exhibit different patterns of expression in the CNS,suggesting distinct functions for each receptor. mGluR5 receptors areexpressed with high to moderate density in frontal cortex, caudate,putamen, nucleus accumbens, olfactory tubercle, hippocampus, and dorsalhorn of the spinal cord, whereas low levels of expression are observedin the cerebellum. In contrast, mGluR1 receptor is expressed in highdensity in the cerebellum, but low to moderate expression is observed infrontal cortex, caudate, putamen, nucleus accumbens, and olfactorytubercle. Therefore it is understood that allosteric modulatorsselective for mGluR1 might produce physiological effects distinct fromthose produced by allosteric modulators selective for mGluR5.

Negative allosteric modulators with affinity for either mGluR1 or mGluR5will produce effects at the receptor which may include the induction ofa change in receptor conformation resulting in a diminished affinity ofthe endogenous ligand for the primary binding site, and decrease ofphysiologic function of the activated receptor. Such functionalmodulation may lead to decreased phosphoinositide hydrolysis, decreasedmobilization of intracellular Ca²⁺, and decreased activation of proteinkinase C.

Conversely, positive allosteric modulators with affinity for eithermGluR1 or mGluR5 might produce effects at the receptor which may includean enhancement of affinity of the endogenous ligand for the primarybinding site or a subsequent enhancement of the normal physiologicfunction of the activated receptor.

The present invention is directed to methods of treating a disease ordisorder which is mediated fully or in part by mGluR1 or mGluR5 usingcompounds of Formula I, and pharmaceutically acceptable salts, prodrugs,enantiomers, or hydrates thereof:

whereinR₁=H, SH, or OR₆;R₂ and R₃ are selected from fused phenyl, H, lower alkyl, I, Br, Cl, F,CF₃, CH₂CF₃, CH₂Ph, CH═CH₂, C≡CH, OCH₃, OCF₃, Ph, OPh, and NO₂;R₄ is selected from the group consisting of H, lower alkyl, I, Br, Cl,F, CF₃, CH₂CF₃, CH₂Ph, CH═CH₂, C≡CH, C≡N, OCH₃, OCF₃, Ph, OPh, and NO₂;R₅ is H, lower alkyl, or phenyl;R₆ is selected from the group consisting of H, COCH₃, COCH₂CH₃,COCH(CH₃)₂, COC(CH₃)₃, COPh, COCH₂Ph, COC₆H₄NO2(p), COC₆H₄OH(p),COC₆H₄NH₂(p), CON(CH₃)₂, CON(CH₂CH₃)₂, CON(CH₃)(CH₂CH₃), CON(CH₂Ph)₂,CON(CH₃)(CH₂Ph), 1-pyrrolidinecarbonyl, 2-carboxy-1-pyrrolidincarbonyl,(2S)-2-carboxy-1-pyrrolidinecarbonyl,(2R)-2-carboxy-1-pyrrolidinecarbonyl, 1-morpholinecarbonyl,4-methyl-1-piperazinecarbonyl, sarcosine-N-carbonyl, CO-N-Me-Ala-OH,CO-N-Me-Val-OH, CO-N-Me-Leu-OH, CO-N-Me-Ile-OH, CO-N-Me-Val-OH,CO-N-Me-Met-OH, CO-N-Me-Phe-OH, CO-N-Me-Trp-OH, CO-Pro-OH,CO-N-Me-Gly-OH, CO-N-Me-Ser-OH, CO-N-Me-Thr-OH, CO-N-Me-Cys-OH,CO-N-Me-Tyr-OH, CO-N-Me-Asn-OH, CO-N-Me-Gln-OH, CO-N-Me-Asp-OH,CO-N-Me-Glu-OH, CO-N-Me-Lys-OH, CO-N-Me-Arg-OH, CO-N-Me-His-OH,CO-N-Me-Gly-Gly-OH, CO-N-Me-Gly-Phe-OH, CO-N-Me-Gly-Glu-OH,CO-N-Me-Gly-Glu-Glu-OH, CO-N-Me-Glu-Glu-OH, CO-N-Me-Gly-Lys-OH,CO-N-Me-Gly-Lys-Lys-OH, CO-Pro-Glu-OH, CO-Pro-Glu-Glu-OH, CO-Pro-Gly-OH,CO-Pro-Gly-Lys-OH, and CO-Pro-Lys-Lys-OH;X is O or S; andZ is substituted phenyl, or substituted 5- or 6-membered heterocyclicring containing 1 or 2 heteroatoms chosen from N, O, and S, wherein saidphenyl substituents are selected from the group consisting of H, loweralkyl, I, Br, Cl, F, CF₃, CH₂CF₃, CH₂Ph, CHPh₂, CH═CH₂, E-CH═CHCH₃,Z—CH═CHCH₃, C≡CH, C≡N, OCH₃, OCF₃, OPh, and NO₂ and wherein saidheterocyclic ring substituents are selected from the group consisting ofH, lower alkyl, I, Br, Cl, F, CF₃, CH₂CF₃, CH₂Ph, CH═CH₂, C≡CH, C≡N,OCH₃, OCF₃, Ph, OPh, and NO₂.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. When thecompound of the present invention is acidic, salts may be prepared frompharmaceutically acceptable non-toxic bases, including inorganic andorganic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,potassium, sodium, and zinc salts, and the like. Salts in the solid formmay exist in more than one crystal structure, and may also be in theform of hydrates. Salts derived from pharmaceutically acceptable organicnon-toxic bases include, but are not limited to, salts of primaryamines, secondary amines, tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, arginine,betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine,2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include, but are not limited to,1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid(L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoricacid(+), camphor-10-sulfonic acid (+), capric acid (decanoic acid),orotic acid, caproic acid (hexanoic acid), caprylic acid (octanoicacid), carbonic acid, cinnamic acid, citric acid, cyclamic acid,dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid,formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonicacid (D), gluconic acid (D), glucuronic acid (D), glutamic acid,glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid,hydrobromic acid, hydrochloric acid, isobutyric acid, isethionic acid,lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid(L), malonic acid, mandelic acid (DL), methanesulfonic acid, mucic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinicacid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid,pantothenic acid, phosphoric acid, propionic acid, pyroglutamic acid(L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuricacid, tartaric acid (L), thiocyanic acid, p-toluenesulfonic acid, andundecylenic acid. It will be understood that, as used herein, compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

The term “fused phenyl” refers to an compound in which two of the carbonatoms of a benzene ring are shared in a larger structure. Non-limitingexamples include 1-naphthol, in which a benzene ring can be visualizedas fused at carbons 2 and 3 of phenol, and1,2,3,4-tetrahydronaphthaline, which can be visualized as benzene fusedto cyclohexene.

The term “radical” refers to a chemical array of atoms which is bondedto another atom in a compound of the invention. The radical is a domainof a molecule described herein, and is not intended to be understood asa separate chemical entity, but rather a substituent or substituentarray of atoms which is a part of a molecule of the invention. A radicalas used herein is not intended to be understood to have ionic charge orsinglet or triplet character, but rather covalently bonded to anotherdomain of the compound of the invention. Stylistic depictions ofradicals herein are intended solely to illustrate certain embodiments ofthe invention.

The term “lower alkyl” means straight-chain or branched hydrocarbonradicals containing 6 or fewer carbons. Examples include, but are notlimited to, methyl, ethyl, propyl, butyl, isopropyl, and tert-butyl,signified by CH₃, CH₂CH₃, CH₂CH₂CH₃, (CH₂)₃CH₃, CH(CH₃)₂, and C(CH₃)₃,respectively. Further examples include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

The term “EC₅₀” refers to the concentration of test compound or agonistat which response is halfway between baseline and maximum. Likewise,“EC₈₀” refers to the concentration of compound (usually agonist) atwhich response is eighty percent of maximum.

Dialkylaminocarbonyl radicals, or secondary amine carbamoyl radicals,are those in which a dialkylamino substituent is joined to another atomby a carbonyl group, designated herein as CO. One example not intendedto be limiting is diethylaminocarbonyl, in which N(CH₂CH₂)₂ is joinedthrough a CO bond to an atom of another molecule, for example to theoxygen of phenol, to form a carbamate derivative. The product,C₆H₅OCONH(CH₂CH₃)₂, contains the CON(CH₂CH₂)₂ radical. A secondnon-limiting example is the 1-pyrrolidinecarbonyl radical, stylisticallyrepresented by A, when bonded to the oxygen of phenol, gives thecarbamate product B, which contains the 1-pyrrolidinecarbonyl radical.

The secondary amine from which the dialkylaminocarbonyl radical isderived might be an N-alkyl amino acid. The terminology used herein todescribe such radicals utilizes the well-known abbreviations for aminoacids, coupled with widely used descriptors indicating N(α)-alkyl aminoacids. The three letter codes for the naturally occurring amino acids(Eur. J. Biochem. 138:9-37 (1984)) are used herein. The secondary aminederived from naturally occurring amino acids, which gives rise to thesaid dialkylaminocarbonyl radicals, is described herein as anabbreviation encompassing the accepted three-letter amino acidabbreviations with the prefix N-Me. Thus, the secondary amine from whichthe dialkylaminocarbonyl radical is derived is referred to herein asN-Me-XXa-OH where Me denotes methyl and Xaa denotes generically anythree-letter abbreviation for a naturally-occurring amino acid. Thethree-letter codes for the amino acids are widely known and can be foundin Lehninger, Biochemistry, (Worth Publishers, New York, N.Y., 1978).The corresponding dialkylaminocarbonyl radical is referred to herein asCO—N-Me-Xaa-OH. As examples not intended to be limiting, theCO—N-Me-Ala-OH radical (wherein Xaa=Ala) has the stylized structure

and the CO—N-Me-Leu-OH radical (wherein Xaa=Leu) has the stylizedstructure

In likewise fashion, the secondary amine from which thedialkylaminocarbonyl radical is derived might be a di- or tri-peptide ordi- or -tri-pseudopeptide, optionally with an N-alkylated N-terminus.For a dipeptide radical, the corresponding dialkylaminocarbonyl radicalis referred to herein as CO—N-Me-Xaa-Xaa-OH. Thus, theCO—N-Me-Gly-Gly-OH radical can be represented as

The stylized depictions of dialkylaminocarbonyl radicals herein are notmeant to reflect actual chemical species, but are rather offered as ameans to better understand the invention and the nomenclature usedherein to describe the various embodiments. It will be understood thatcompounds of the invention containing amino acids refers to the natural(L) form, the (D) form, and the racemic (D,L) form.

In some embodiments, compounds of Formula I comprise

In some embodiments of the invention, compounds of Formula 1 comprise

whereinR1=OH;R2 and R3=H;R4 is selected from the set consisting of H, Cl, Br, F, CH3, OCH3, CF3,OCF3, and phenyl;R5=H; andR7, R8, R9, and R10 are each independently chosen from the groupconsisting of Cl, Br, F, CH3, CH2CH3, CH2Ph, CH═CH₂, C≡CH, C≡N, OCH₃,OCF₃, Ph, OPh, and NO₂.

In some embodiments of the invention, compounds of Formula 1 comprise

Compounds of Formula 1 which have little or no inherent binding affinityfor either the orthosteric or allosteric sites of Group 1 mGluRs arecontemplated and provided in the invention. Such compounds arederivatives of active elements of Formula 1 which are designed todegrade in a controlled fashion under conditions of use of compounds ofthe invention, ultimately providing an active agent of Formula 1. Thesederivatives of the active compounds of Formula 1, herein termed“prodrugs”, are useful in that their chemical structure, althoughdemonstrating little or no binding affinity, imparts properties ofparticular importance in the treatment of diseases or disorders mediatedfully or partially by Group 1 mGluRs as disclosed herein. Suchproperties include, but are not limited to, enhancement of solubility inaqueous systems, improvement of pharmacokinetic parameters, improvementof purification procedures, enhancement of membrane permeability, andthe provision of controlled release of the active principle. Thedegradation of the inert derivative to the active compound of Formula 1may occur by simple chemical hydrolysis. Alternatively, said derivativemay be a substrate for an enzyme which provides the active compound.Derivatives are chosen so that the chemical bond is cleavable underphysiological conditions, whether chemical or enzymatic. In the case ofthe present invention, active compounds of Formula 1 possess a freephenolic —OH, and prodrug derivatives are esters or carbamates. It iswell known in the art that certain inactive prodrug esters andcarbamates of hydroxyl-containing drugs yield the drug afteradministration to a subject. For example, Dipivefrin, an inactiveprodrug containing two tert-butyl esters, is cleaved to the drugadrenaline after administration to a subject, and valacyclovir, a valineester, is cleaved to acyclovir after administration. For anotherexample, the inactive prodrug bis(dimethylcarbamate) bambuterol isconverted to the [beta]₂-sympathomimetic agent terbutaline used toachieve bronchodilation in the management of asthma. Terbutaline isformed from bambuterol by hydrolysis predominantly catalyzed by plasmacholinesterase (pChE, EC 3.1.1.8) (Nyberg, L. et al, Br. J. Clin.Pharmacol. 1998; 45(5); 471-8.

In some embodiments, prodrug compounds of Formula 1 comprise

whereinR4 is selected from the set consisting of H, Cl, Br, F, CH₃, OCH₃, CF₃,OCF₃, and phenyl;R₆ is selected from the group consisting of COCH₃, COCH₂CH₃, COCH(CH₃)₂,COC(CH₃)₃, COPh, COCH₂Ph, COC₆H₄NO2(p), COC₆H₄OH(p), COC₆H₄NH₂(p),CON(CH₃)₂, CON(CH₂CH₃)₂, CON(CH₃)(CH₂CH₃), CON(CH₂Ph)₂, CON(CH₃)(CH₂Ph),1-pyrrolidinecarbonyl, 2-carboxy-1-pyrrolidincarbonyl,(2S)-2-carboxy-1-pyrrolidinecarbonyl,(2R)-2-carboxy-1-pyrrolidinecarbonyl, 1-morpholinecarbonyl,4-methyl-1-piperazinecarbonyl, sarcosine-N-carbonyl, CO-N-Me-Ala-OH,CO-N-Me-Val-OH, CO-N-Me-Leu-OH, CO-N-Me-Ile-OH, CO-N-Me-Val-OH,CO-N-Me-Met-OH, CO-N-Me-Phe-OH, CO-N-Me-Trp-OH, CO-Pro-OH,CO-N-Me-Gly-OH, CO-N-Me-Ser-OH, CO-N-Me-Thr-OH, CO-N-Me-Cys-OH,CO-N-Me-Tyr-OH, CO-N-Me-Asn-OH, CO-N-Me-Gln-OH, CO-N-Me-Asp-OH,CO-N-Me-Glu-OH, CO-N-Me-Lys-OH, CO-N-Me-Arg-OH, CO-N-Me-His-OH,CO-N-Me-Gly-Gly-OH, CO-N-Me-Gly-Gly-Gly-OH, CO-N-Me-Gly-Phe-OH,CO-N-Me-Gly-Glu-OH, CO-N-Me-Gly-Glu-Glu-OH, CO-N-Me-Glu-Glu-OH,CO-N-Me-Gly-Lys-OH, CO-N-Me-Gly-Lys-Lys-OH, CO-Pro-Glu-OH,CO-Pro-Glu-Glu-OH, CO-Pro-Gly-OH, CO-Pro-Lys-OH, CO-Pro-Lys-Lys-OH,CO-Pro-Gly-Lys-OH, and CO-Pro-Lys-Lys-OH; andR7, R8, R9, and R10 are each independently chosen from the groupconsisting of Cl, Br, F, CH₃, CH₂CH₃, CH₂Ph, CH═CH₂, C≡CH, C≡N, OCH₃,OCF₃, Ph, OPh, and NO₂.

It will be appreciated that other amino acids not specificallyidentified herein might be utilized in prodrug compounds of Formula 1.These may be selected from the family of naturally occurring L-aminoacids, that is, alanine, valine, leucine, isoleucine, proline,phenylalanine, tryptophan, methionine, glycine, serine, threonine,cysteine, cystine, tyrosine, asparagine, glutamine, aspartic acid,glutamic acid, lysine, arginine, and histidine. It will also beappreciated that, in addition to the L-amino acids herein described,unnatural D-amino acids may be employed in prodrug compounds ofFormula 1. It will be further appreciated that, in addition to thespecific prodrugs of Formula 1 disclosed herein, other peptide prodrugsare contemplated by the present invention. These include, but are notlimited to, di-, tri-, tetra-, penta-, hexa-, hepta, octa-, nona-, anddeca-peptides comprised of any of the natural L-amino acids or theunnatural D-amino acids or their N-methyl derivatives.

In some embodiments, prodrug compounds of Formula 1 comprise

Prodrug derivative compounds of Formula 1 can be transformed intopharmaceutically acceptable salts by means well known to those withskill in the art. Such salts are intended to provide enhanced propertiessuch as increased water solubility. Such salts are contemplated by theinvention and provided herein. Such salts may be prepared by methodswell-known to those with skill in the art. For example, an acidicprodrug derivative compound of Formula 1 may be dissolved in a solventsuch as, inter alia, methanol, ethanol, or tetrahydrofuran and a molarequivalent amount of meglumine added to form the addition salt. Removalof the solvent or precipitation of the salt by addition of a cosolventsuch as, inter alia, ether, petroleum ether, hexane, heptane, or tolueneprovides the purified salt. Alternatively, such salts may be prepared bymethods disclosed in U.S. Pat. No. 5,028,625 to Motola et al.Alternatively, such salts may be prepared by methods disclosed inWO/2007/063335 to Klaveness.

In some embodiments of the invention, pharmaceutically acceptable saltsof prodrug derivative compounds of Formula 1 comprise

Compounds of Formula I are useful in modulating the functional action ofGroup I metabotropic glutamate receptors. Compounds of Formula I areuseful in preventing and treating diseases or disorders caused bydysfunctional Group I metabotropic glutamate receptors. The ability ofcompounds of Formula I to act as allosteric modulators of thesereceptors can be assessed by measuring the degree of binding of a ligandto the orthosteric glutamate binding site in the presence of a compoundof Formula I. Binding of a compound of Formula I to an allosteric sitecan induce a change in the conformation of the receptor, which in turncan influence the affinity of an orthosteric ligand for the primary(glutamate) receptor site. For example, the binding constant (K) of aligand such as quisqualate (quisqualic acid,(2S)-2-amino-3-(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)propanoic acid) canbe altered if a compound of Formula I is bound to an allosteric bindingsite. The K_(i) of the orthosteric ligand can be measured usingradiolabelled ligand (for example ³H-quisqualate) by methods well knownin the art. Assays of such altered orthosteric binding are commerciallyavailable (offered, for example, by Euroscreen SA, Gosselies, BE). Theability of compounds of Formula I to act as allosteric modulators ofGroup I metabotropic glutamate receptors can also be assessed by theability of a compound to displace a known allosteric ligand, as twodifferent ligands may compete for an allosteric binding site. Forexample, the ability of compounds of Formula I to function as allostericligands to mGluR1 may be assessed by their ability to displace the knownmGluR1 allosteric ligand R214127. This may be measured by methods knownin the art (Lavreysen, H. et al 2003; Mol. Pharmacol. 63:1082-1093). Foran additional example, the ability of compounds of Formula I to functionas allosteric ligands to mGluR5 may be assessed by their ability todisplace the known mGluR5 allosteric ligand MPEP(2-methyl-6-(phenylethynyl)-pyridine). This may be measured by methodsknown in the art (Gasparini, F. et al 2002; Bioorg. Med. Chem. Lett.12:407-409; Anderson, F. et al. 2002; J. Pharmacol. Exp. Ther.303:1044-1051). Such measurement by displacement of MPEP by compounds ofFormula I are commercially available (from, for example, Euroscreen SA,Gosselies, BE). The ability of compounds of Formula I to act asallosteric modulators of Group I metabotropic glutamate receptors canalso be assessed by the ability of a compound to influence the functionof the Group I metabotropic glutamate receptors. This may be measured bymethods known in the art. For example, the measurement of the ability ofa compound of Formula I to modulate Group I metabotropic glutamatereceptors may be assessed by its ability to inhibit glutamate-inducedphosphoinositide accumulation (Pin, J. et al 1995; Neuropharm. 34:1-26;Sortino, M. et al 1991; Brain Res. Dev. Brain Res. 61:169-172.). Anotherexample of the ability of a compound of Formula I to modulate Group Imetabotropic glutamate receptors may be assessed by its ability toinhibit glutamate-induced calcium release (Chen, Y et al 2007; Mol.Pharmacol. 71:1389-1398; Malherbe, P. et al 2003; Mol. Pharmacol.64:823-832.)

The ability of compounds of Formula I to prevent or treat diseases ordisorders of the central nervous system may be assessed by meanswell-known in the art. For example, a variety of preparations of centralnervous system receptors have been described. The affinity of compoundsof Formula I for such receptors, and the determination of agonism orantagonism displayed by compounds of Formula I relative to suchreceptors, is quantifiable. In addition, there are several animal modelsof human central nervous system disorders or diseases which may assaythe activity of Compounds of Formula I (offered, for example, byNeuroDetective International, Wyncote, Pa.).

Compounds of Formula I are useful in a method of modulating Group Imetabotropic glutamate receptor activity in a mammal in need of suchmodulation comprising the administration of an effective amount of thecompound. The present invention is directed to the use of the compoundsdisclosed herein as modulators of metabotropic glutamate receptoractivity. In addition to primates, especially humans, a variety of othermammals can be treated according to the method of the present invention.

In a like manner, the noncompetitive antagonist compounds of Formula Iare useful in a method of inhibiting metabotropic glutamate receptoractivity in a mammal in need of such inhibition comprising theadministration of an effective amount of the compound. The presentinvention is directed to the use of the compounds of Formula I asnoncompetitive antagonists of Group I metabotropic glutamate receptoractivity. In addition to primates, especially humans, a variety of othermammals can be treated according to the method of the present invention.

Compounds of Formula 1 were found to bind with varying affinity andselectivity to mGluR1 and mGluR5. Briefly, stable recombinant cell linesexpressing mGluR1 or mGluR5 and aequorin were treated with compounds ofFormula 1 at various concentrations. The ability of test compound toameliorate the efflux of calcium cations (Ca⁺⁺) in the presence ofagonist (glutamate or quisqualate) is measured by detection of lightemitted by the luminescent protein aequorin triggered by binding of Ca⁺⁺. Aequorin is a photoprotein isolated from luminescent jellyfish (likevarious Aequorea species e.g. Aequorea victoria). Aequorin is composedof two distinct units, the apoprotein apoaequorin, with an approximatemolecular weight of 22 kDa, and the prosthetic group, coelenterazine,responsible for emission of light. In the presence of molecular oxygenthe two components of aequorin assemble spontaneously, forming thefunctional protein. Four EF-hand type regions have been identified inthe structure of Aequorin and at least 3 of them function as bindingsites for Ca+2 ions: Ca+2 binding to these EF hands triggers aconformational change of the protein, that leads it to oxidize itsprosthetic group, coelenterazine, into excited coelenteramide and CO2.As the excited coelenteramide relaxes to the ground state, blue light(wavelength=469 nm) is emitted and can be measured by a luminometer.Negative allosteric modulator activity of test compound is expressed asa percentage of the stimulation of reference agonist (glutamate)activity at its EC₈₀ concentration. Assay of Compounds was performed atEuroscreen SA, Gosselies, Belgium.

The in vitro binding of compounds of Formula 1 to mGluR1 and/or mGluR5,as determined by the aequorin assay, is a measure of the potential ofthese compounds to treat diseases and disorders partially or fullymodulated by mGluR1 and/or mGluR5. It is understood that the magnitudeof affinity of a compound for a Group 1 mGluR may not reflect itssuitability as a therapeutic agent to treat diseases and disorders fullyor partially mediated by Group 1 mGluRs. This is because metabotropicglutamate receptors mediate a wide variety of normal physiologicalprocesses, and agents which block the functionality of these receptorsmay produce pathological effects. Some disorders, for example, interalia, central nervous system disorders, may be best treated with anegative allosteric modulator with moderate affinity for Group 1 mGluRs.Compounds of Formula 1 provided by the invention are intended to beeffective therapeutic agents for treatment of diseases or disordersfully or partially mediated by Group 1 mGluRs. Compounds of Formula 1with EC₅₀ in the range of 0.1 to 1000 nM are considered effectivenegative allosteric modulators. In some embodiments, compounds with EC₅₀in the range of 1 to 1000 nM are considered effective negativeallosteric modulators. In other embodiments, compounds with EC₅₀ in therange of 10 to 1000 nM are considered effective negative allostericmodulators. In still other embodiments, compounds with EC₅₀ in the rangeof 30 to 1000 nM are considered effective negative allostericmodulators. In yet other embodiments, compounds with EC₅₀ in the rangeof 100 to 1000 nM are considered effective negative allostericmodulators.

It was surprisingly discovered that some compounds of Formula 1exhibited selective affinity for one of the Group1 mGluRs. It isunderstood that some diseases or disorders fully or partially mediatedby Group 1 mGluRs may be best treated with compounds which selectivelyantagonize mGluR1 or mGluR5. It is also understood that some diseases ordisorders fully or partially mediated by Group 1 mGluRs may be besttreated with compounds which demonstrate little selectivity and whichantagonize both mGluR1 and mGluR5. A measure of the selective affinityof the compounds of Formula 1 for these receptors can be made bystriking a ratio of the EC₅₀ values. For any compound, the EC₅₀ formGluR1 divided by the EC₅₀ for mGluR5 provides such a ratio. Thus,compounds with such a ratio less than 1.0 demonstrate selective affinityfor mGluR1, and compounds with a ratio greater than 1.0 demonstrateselective affinity for mGluR5. In some embodiments, a compound ofFormula 1 with a mGluR5/mGluR1 EC₅₀ ratio in the range of 0.01 to 0.8 isconsidered selective for mGluR1. In some embodiments, a compound ofFormula 1 with a mGluR5/mGluR1 EC₅₀ ratio in the range of 1.25 to 100 isconsidered selective for mGluR5.

TABLE 1 Table 1 depicts the affinities and mGluR5/mGluR1 EC₅₀ ratio ofrepresentative compounds of Formula 1 having the structure

mGluR1 mGluR5 EC₅₀ EC₅₀ mGluR1/mGluR5 Compound R1 R2 R3 R4 R7 R8 R9 R10nM nM Ratio 1 OH H H Cl Cl H NO₂ H 38 62 0.61 2 OH Cl H Cl Cl H NO₂ H1577 669 2.36 3 OH fused phenyl H Cl H NO₂ H 603 262 2.30 4 OH H H H ClH NO₂ H 290 168 1.73 5 OH H H Cl H Cl Cl H 179 90 1.99 6 OH H H Cl H H HH 3041 731 4.16 7 OH H H Cl H H NO₂ H 300 169 1.78 8 OH H H Cl H CH₃ H H2386 84 28.40 9 OH H H Cl H Br H H 459 166 2.77 10 OH H H Cl H C≡CH H H932 122 7.64 11 OH H H Cl H CH═CH₂ H H 371 48 7.73 12 OH H H Cl H CH₂CH₃H H 859 135 6.36 13 OH H H Cl H CF₃ H H 273 127 2.15 14 OH H H Cl H Cl HH 523 126 4.15 15 OH H H Cl H OCH₃ H H 10000 260 38.46 16 OH H H Cl H CNH H 10000 235 42.55 17 OH H H Cl H F H H 598 138 4.33 18 OH H H Cl HC(CH₃)₃ H H 334 238 1.40 19 OH H H Cl H CH₃ H CH₃ 1145 122 9.39 20 OH HH Cl H CF₃ H CF₃ 111 91 1.22 21 CH₃CO(═O) H H Cl H H NO₂ H 94 91 1.03 22PhC(═O)O H H Cl H H NO₂ H 192 109 1.76 23 (CH₃)₂NC(═O)O H H Cl H H NO2 H10000 10000 NA 24

H H Cl H H NO₂ H 95 59 1.61 25

H H Cl H H NO₂ H 10000 10000 NA 26

H H Cl H H NO₂ H 10000 10000 NA 27

H H Cl H H NO₂ H 10000 10000 NA NA = not applicable. Values designatedas 10000 indicate no activity was observed at 10,000 nM (10 μM).It should be emphasized than the phenolic ester functionality(ArO(C═O)C) in compounds 21, 22, and 24 is sensitive to simple chemicalhydrolysis. In addition, compounds containing this functionality may besubstrates for esterase enzymes potentially present in the cell-basedassay. Therefore, although these compounds may exhibit no inherentactivity, hydrolysis or enzymatic cleavage under the conditions of theassay may provide Compound 1 which has potent binding activity, and theapparent activity of the ester compounds may be due to Compound 1liberated from its ester derivatives in the course of the assay.

In addition to the salicylanilide derivatives depicted in Table 1, itwas surprisingly found that certain thiazole derivatives of benzamidedemonstrated in vitro activity. For example,

demonstrated binding of 6320 nM at mGluR1 and 2764 nM at mGluR5, and

demonstrated binding of 1759 nM at mGluR1 and 1254 nM at mGluR5.

As demonstrated herein, compounds of Formula I possess in vitro bindingaffinity for the Group 1 mGluRs and thus are useful in the treatment ofdiseases or disorders mediated by Group 1 mGluRs.

Certain compounds of Formula I were further evaluated for their abilityto mediate neuropathic pain in a partial sciatic nerve ligation assay inthe rat (Y. Shir and Z. Seltzer 1990; Neurosci. Lett., 115:62-7).Briefly, under gas anesthesia, the skin and muscles of the thigh werereflected to expose the sciatic nerve. About one-third to one-half ofthe cross-sectional area of the nerve was tightly ligated using a 7-0nylon suture. The incision was closed in layers (suture for muscle,surgical adhesive for skin). After a three-week recovery, the animalswere dosed with either 10 or 49 μg Compound 1, 10 or 49 μg Compound 21,or 100 μg gabapentin by intrathecal injection. Treated rats were assayedat 1, 3, 5, and 24 hr using the paw withdrawal method (L. Randall and J.Selitto, 1957, Arch. Int. Pharmacodynam., 111:409-19). As presentedgraphically in FIG. 1 and tabulated in Table 2, Compound 1 and Compound21 were essentially as effective or more effective as gabapentin inreversing hyperalgesia. As illustrated in FIG. 1 and presented in Table2, 49 μg of Compound 1 (0.15 μMol), is considerably more effective than100 μg (0.58 μMol) gabapentin in this model of hyperalgesia. Indeed, 49μg of Compound 21 (0.18 μMol) is nearly equipotent with 100 μg (0.58μMol) gabapentin in the model. The Partial sciatic nerve ligation assaywas performed at Eurofins/Product Safety Laboratories (Dayton, N.J.).

TABLE 2 Paw Withdrawal data. Paw withdrawal thresholds (g; raw data)Pre- Pre- Raw MPE (%) % MPE (0-100) AUC Rat Group injury Dose 1 hr 3 hrs5 hrs 24 hrs 1 hr 3 hrs 5 hrs 24 hrs 1 hr 3 hrs 5 hrs 24 hrs AUC (0-5) 1PSN Sx/ 125 80 85 90 90 95 7 Vehicle 165 130 150 125 115 130 12 160 130115 120 130 120 21 165 65 70 65 75 75 24 200 90 100 105 95 75 37 130 95105 100 95 75 40 155 85 70 100 80 85 Average 157.1 96.4 99.3 100.7 97.193.6 SD 25.0 24.8 28.2 19.9 19.3 22.9 SEM 9.4 9.4 10.7 7.5 7.3 8.6 N 7 77 7 7 7 31 Sham Sx/ 125 160 220 175 160 165 33 Vehicle 140 165 160 170200 200 36 160 145 150 175 160 155 39 165 185 165 150 155 145 41 190 195190 185 180 160 45 155 150 220 170 180 160 Average 155.8 166.7 184.2170.8 172.5 164.2 SD 22.2 19.7 30.7 11.6 17.2 18.8 SEM 9.1 8.0 12.5 4.77.0 7.7 N 6 6 6 6 6 6 2 PSN Sx/ 155 125 90 130 120 125 −10.9 41.8 30.344.5 0.0 41.8 30.3 44.5 113.9 14 SND 150 85 90 120 120 105 −10.9 27.530.3 16.2 0.0 27.5 30.3 16.2 85.3 20 121, 10 μg 150 60 60 100 70 95−46.3 −1.0 −36.0 2.0 0.0 0.0 0.0 2.0 0.0 22 160 105 105 100 130 100 6.7−1.0 43.6 9.1 6.7 0.0 43.6 9.1 53.7 23 160 95 250 180 195 195 177.6113.1 129.9 143.7 100.0 100.0 100.0 100.0 450.0 46 130 70 160 150 100 8571.5 70.3 3.8 −12.1 71.5 70.3 3.8 0.0 251.7 Average 150.8 90.9 125.8130.0 122.5 117.5 31.3 41.8 33.6 33.9 29.7 39.9 34.7 28.6 159.1 SD 11.123.7 69.2 31.0 41.4 40.2 81.5 44.2 55.0 57.0 44.4 39.7 36.2 38.5 165.6SEM 4.5 9.7 28.2 12.6 16.9 16.4 33.3 18.0 22.5 23.3 18.1 16.2 14.8 15.767.6 N 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 9 PSN Sx/ 165 90 250 250 180 90177.6 212.9 110.0 −5.1 100.0 100.0 100.0 0.0 450.0 17 SND 121, 49 μg 19055 250 150 130 55 177.6 70.3 43.6 −54.6 100.0 70.3 43.6 0.0 334.2 18 180115 190 90 100 100 106.9 −15.3 3.8 9.1 100.0 0.0 3.8 9.1 153.8 27 140 80140 130 80 80 48.0 41.8 −22.7 −19.2 48.0 41.8 0.0 0.0 155.5 35 150 90130 110 95 90 36.2 13.2 −2.8 −5.1 36.2 13.2 0.0 0.0 80.8 44 160 95 235250 130 90 159.9 212.9 43.6 −5.1 100.0 100.0 43.6 0.0 393.6 Average164.2 87.5 199.2 163.3 119.2 84.2 117.7 89.3 29.2 −13.3 80.7 54.2 31.81.5 261.3 SD 18.6 19.7 54.4 70.0 35.8 15.6 64.1 99.9 47.6 22.1 30.1 43.039.3 3.7 150.8 SEM 7.6 8.0 22.2 28.6 14.6 6.4 26.2 40.8 19.4 9.0 12.317.5 16.1 1.5 61.6 N 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 8 PSN Sx/ 135 110 250190 140 95 177.6 127.3 56.9 2.0 100.0 100.0 56.9 2.0 406.9 16 SND 182,10 μg 125 80 130 140 110 105 36.2 56.0 17.1 16.2 36.2 56.0 17.1 16.2183.4 26 165 90 210 145 145 90 130.4 63.2 63.5 −5.1 100.0 63.2 63.5 0.0339.8 38 175 95 200 100 70 55 118.7 −1.0 −36.0 −54.6 100.0 0.0 0.0 0.0150.0 42 165 65 130 85 100 85 36.2 −22.4 3.8 −12.1 36.2 0.0 3.8 0.0 58.143 160 85 120 130 70 75 24.4 41.8 −36.0 −26.3 24.4 41.8 0.0 0.0 120.1Average 154.2 87.5 173.3 131.7 105.8 84.2 87.2 44.1 11.5 −13.3 66.1 43.523.5 3.0 209.7 SD 19.6 15.1 53.9 37.0 32.6 17.4 63.5 52.7 43.3 24.7 37.438.8 29.2 6.5 135.0 SEM 8.0 6.2 22.0 15.1 13.3 7.1 25.9 21.5 17.7 10.115.2 15.8 11.9 2.7 55.1 N 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 10 PSN Sx/ 14590 250 250 190 110 177.6 212.9 123.2 23.3 100.0 100.0 100.0 23.3 450.011 SND 182, 49 μg 125 95 160 125 140 160 71.5 34.6 56.9 94.1 71.5 34.656.9 94.1 233.4 13 125 70 65 60 85 90 −40.4 −58.1 −16.1 −5.1 0.0 0.0 0.00.0 0.0 19 160 120 250 105 120 80 177.6 6.1 30.3 −19.2 100.0 6.1 30.30.0 192.6 29 150 55 135 65 60 45 42.1 −50.9 −49.3 −68.8 42.1 0.0 0.0 0.063.1 50 130 95 100 130 85 100 0.8 41.8 −16.1 9.1 0.8 41.8 0.0 9.1 84.8Average 139.2 87.5 160.0 122.5 113.3 97.5 71.5 31.1 21.5 5.6 52.4 30.431.2 21.1 170.6 SD 14.6 22.5 76.7 69.0 47.1 37.9 90.4 98.5 62.5 53.745.6 38.5 40.8 36.9 161.6 SEM 6.0 9.2 31.3 28.2 19.2 15.5 36.9 40.2 25.521.9 18.6 15.7 16.6 45.1 66.0 N 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 3 PSN Sx/120 110 145 70 60 85 53.9 −43.8 −49.3 −12.1 53.9 0.0 0.0 0.0 80.8 4Gabapentin, 160 65 250 125 130 110 177.6 34.6 43.6 23.3 100.0 34.6 43.623.3 262.9 15 100 μg 140 90 190 125 85 80 106.9 34.6 −16.1 −19.2 100.034.6 0.0 0.0 219.3 28 145 75 100 90 100 75 0.8 −15.3 3.8 −26.3 0.8 0.03.8 0.0 5.1 32 130 85 120 165 140 135 24.4 91.7 56.9 58.7 24.4 91.7 56.958.7 276.8 47 185 125 185 230 65 105 101.0 184.4 −42.7 16.2 100.0 100.00.0 16.2 350.0 Average 146.7 91.7 165.0 134.2 96.7 98.3 77.4 47.7 −0.66.7 63.2 43.5 17.4 16.4 199.1 SD 23.2 22.3 54.6 57.2 33.1 22.7 64.3 81.643.9 32.2 43.7 43.5 25.8 23.0 130.3 SEM 9.5 9.1 22.3 23.4 13.5 9.3 26.333.3 17.9 13.1 17.8 17.8 10.5 9.4 53.2 N 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6PSN/SND-121 is Compound1; PSN/SND-182 is Compound 21; PSN/Vehicle is 9%DMSO/27% Cremophor/64% Saline, Sx is surgery, SD is Standard Deviation,SEM is Standard Error of the Mean, N is Number of Animals, MPE isMaximum Percent Effect

As demonstrated herein, compounds of Formula I possess in vivo bindingactivity as a result of their affinity to bind at Group 1 mGluRs asevidenced by their ability to mediate hyperalgesia and thus are usefulin the treatment of diseases or disorders mediated by Group 1 mGluRs.

The subject treated in the present method is a mammal in whichmodulation, inhibition, or attenuation of Group I metabotropic glutamatereceptor activity is desired. The term “therapeutically effectiveamount” or “effective amount” means the amount of the compound ofFormula I that will provide such modulation, inhibition, or attenuation.

As used herein, the terms “treatment” and “treating” refer to anyprocess wherein there may be a slowing, interrupting, arresting,controlling, ameliorating, lessening, regulating, or stopping of theprogression of the disorders mediated by Group 1 mGluRs including, butnot limited to those described herein, but does not necessarily indicatea total elimination of all symptoms of the disorders. “Treatment” and“treating” may also refer to prophylactic therapy of the disordersmediated by Group 1 mGluRs including, but not limited to those describedherein.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing one ormore compounds of Formula I and a pharmaceutically acceptable carrier.By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be devoid of intrinsic biological activity, and becompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The terms “administration of” and or “administering” a compound shouldbe understood to mean providing a compound of Formula I or a prodrug ofa compound of Formula I or a composition containing a compound orprodrug of a compound of Formula 1 to an individual in need of treatmentby a route generally accepted by those with skill in the art. Routes ofsuch administration include, but are not limited to, oral, buccal,sublingual, inhalation, topical, transcutaneous, intravenous,subcutaneous, intraperitoneal, transdermal, intracerebroventricular,intrathecal, intracerebral implant, and depot implant.

Group I metabotropic glutamate receptors have been implicated in a widerange of biological functions. This has suggested a potential role forthese receptors in a variety of disease processes in humans or otherspecies.

Compounds of Formula I have utility in treating a variety ofneurological and psychiatric disorders associated with glutamatedysfunction, including one or more of the following conditions ordiseases: cognitive disorders including dementia (associated withAlzheimer's disease, ischemia, trauma, vascular problems or stroke, HIVdisease, Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; anxiety disorders including acute stressdisorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition; schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-inducedpsychotic disorder; substance-related disorders and addictive behaviors(including substance-induced delirium, persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder; tolerance,dependence or withdrawal from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine,opioids, phencyclidine, sedatives, hypnotics or anxiolytics); movementdisorders, including akinesias and akinetic-rigid syndromes (includingParkinson's disease, drug-induced parkinsonism, postencephaliticparkinsonism, progressive supranuclear palsy, multiple system atrophy,corticobasal degeneration, parkinsonism-ALS dementia complex and basalganglia calcification), medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesiasincluding tremor (such as rest tremor, postural tremor and intentiontremor), chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea and hemiballism), myoclonus (including generalized myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics), and dystonia (including generalized dystonia such asiodiopathic dystonia, drug-induced dystonia, symptomatic dystonia andparoxysmal dystonia, and focal dystonia such as blepharospasm,oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis,axial dystonia, dystonic writer's cramp and hemiplegic dystonia)];obesity, bulimia nervosa and compulsive eating disorders; pain includingbone and joint pain (osteoarthritis), repetitive motion pain, dentalpain, cancer pain, myofacial pain (muscular injury, fibromyalgia),perioperative pain (general surgery, gynecological), chronic pain,neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraineand migraine headache; obesity or eating disorders associated withexcessive food intake and complications associated therewith;attention-deficit/hyperactivity disorder; conduct disorder; mooddisorders including depressive disorders, bipolar disorders, mooddisorders due to a general medical condition, and substance-induced mooddisorders; muscular spasms and disorders associated with muscularspasticity or weakness including tremors; urinary incontinence;amyotrophic lateral sclerosis; neuronal damage including ocular damage,retinopathy or macular degeneration of the eye, hearing loss ortinnitus; emesis, brain edema and sleep disorders including narcolepsy.Illustrative examples of the neuropathic pain include diabeticpolyneuropathy, entrapment neuropathy, phantom pain, thalamic pain afterstroke, post-herpetic neuralgia, atypical facial neuralgia pain aftertooth extraction and the like, spinal cord injury, trigeminal neuralgiaand cancer pain resistant to narcotic analgesics such as morphine. Theneuropathic pain includes the pain caused by either central orperipheral nerve damage. And it includes the pain caused by eithermononeuropathy or polyneuropathy. Compounds of Formula 1 are intended tobe used for the prevention and/or delay of progression of pain.

In accordance with the present invention, the compounds of Formula I areuseful in the treatment of disorders of the gastro-intestinal andurinary tract. In particular compounds of Formula I are useful in thetreatment of conditions associated with visceral hypersensitivity,discomfort/pain and/or altered motor dysfunctions.

Disorders of the GI tract are well known to the expert. These disordersinclude Gastro-Esophageal Reflux Disease (GERD), FunctionalGastro-intestinal Disorders and Post-operative Ileus. FunctionalGastro-intestinal Disorders (FGIDs) are defined as chronic or recurrentconditions associated with abdominal symptoms without organic causeusing conventional diagnostic measures. A cardinal symptom present inmany FGIDs is visceral pain and/or discomfort. FGIDs include FunctionalDyspepsia (FD), functional heartburn (a subset of GERD), Irritable BowelSyndrome (IBS), Functional Bloating, Functional Diarrhea, ChronicConstipation, Functional Disturbances of the Biliary Tract as well asother conditions (see Gut 1999; Vol. 45 Suppl. II).

Post-operative Ileus is defined as failure of aboral passage ofintestinal contents due to transient impairment of GI motility followingabdominal surgery.

Disorders of the Urinary Tract comprise conditions associated withfunctional disturbances and/or discomfort/pain of the urinary tract.Examples of disorders of the urinary tract include but are not limitedto incontinence, benign prostatic hyperplasia, prostatitis, detrusorhyperreflexia, outlet obstruction, urinary frequency, nocturia, urinaryurgency, overactive bladder (OAB), pelvic hypersensitivity, urgeincontinence, urethritis, prostatodynia, cystitis, idiopathic bladderhypersensitivity and the like. OAB is a syndrome characterized byurgency, with or without urinary incontinence, and usually withincreased voiding frequency and nocturia.

Gastro-Esophageal Reflux Disease (GERD) results from the retrograde flowof gastric contents into the esophagus. It is the most common ailment inthe upper gastro-intestinal tract; its cardinal feature and symptom iscommonly known as “heartburn”. A major factor considered for GERD is anincompetence of the Lower Esophageal Sphincter that opens transientlyand allows passage of material (e.g. meal, acidic fluid or bile), fromthe stomach into the esophagus. This motor event denominated TransientLower Esophageal Sphincter Relaxation (TLESR) occurs more often inpatients suffering from GERD than in healthy subjects and occurs moreoften in infants with regurgitation. Current standard therapies in GERDaim at suppressing gastric acid secretion or enhancing gastrointestinalmotility to limit the exposure of the esophagus to acidic gastriccontents. Frequent exposure of the esophageal mucosa to acid can triggerpain (often perceived as heartburn) and lead to erosions. It can alsolead to extra-esophageal disorders such as asthma, cough and laryngitis.To date, there is no treatment available which reduces the occurrence ofTLESRs and, thereby, the symptoms associated with GERD or regurgitationin infants.

Functional Dyspepsia (FD) is defined as a condition associated with aheterogeneous pattern of upper abdominal symptoms including discomfort,pain, aching, bloating, belching, fullness, early satiety, nausea andvomiting, burning and indigestion Almost 80% of patients with FunctionalDyspepsia have two or more of the above mentioned symptoms of the upperGI tract. The pathophysiological abnormalities observed in FD are asfollows: Impaired gastric accommodation upon meal intake,hypersensitivity to gastric distension, delayed gastric emptying,autonomous and/or central nervous system disorder, exaggerated phasiccontractile activity, abnormalities of the gastric electrical rhythm,duodenal hypersensitivity to lipids or acid, small intestinaldysmotility. Meals evoke symptoms in more than 75% of FD patients, andsymptoms increase with meal ingestion in more than 90% of patients.Therefore, a treatment that prepares the stomach to meal intake has thepotential to reduce meal-evoked symptoms. In fact, low fasting volume(not postprandial volume) was found to be an independent predictor forreduced meal size and post-meal symptoms in FD patients (Delgado-Aros etal., Gastroenterology, 2004; 127:1685-1694).

Irritable Bowel Syndrome (IBS) is a chronic or remittentgastrointestinal illness characterized by symptoms that includeabdominal pain and/or discomfort, bloating and bowel disturbances, whichmay be either diarrhea or constipation or a bowel habit that hasfeatures of both.

Pain and/or Discomfort is often associated with FGIDs, disorders of theurinary tract and post-operative ileus; it is not only a symptom ofGERD. Patients suffering from Irritable Bowel Syndrome (IBS), dyspepsia,diseases of the biliary tract, pancreas, urinary bladder andpost-operative conditions report pain and discomfort. Visceralhypersensitivity has been discovered as a key phenomenon in manypatients suffering from conditions like IBS, dyspepsia, GERD, functionalheartburn and other conditions listed above. To date, there is nomedication available which specifically treats visceral hypersensitivityand, thereby, reduces symptoms of pain/discomfort in patients sufferingfrom GERD, functional heartburn, IBS, dyspepsia, diseases of the biliarytract, pancreas, urinary bladder and post-operative conditions. Pain, asused in this specification, includes visceral pain and/or visceraldiscomfort.

A further aspect of the invention relates to the use of compounds ofFormula I for the treatment of FGIDs (e.g., functional heartburn, FD,IBS).

A further aspect of the invention relates to the use of compounds ofFormula I for the treatment of disorders of the urinary tract.

A further aspect of the invention relates to the use of compounds ofFormula I for the treatment of post-operative ileus.

A further aspect of the invention relates to the use of compounds ofFormula I for the treatment of pain associated with disorders of thegastrointestinal and urinary tract.

A further aspect of the invention relates to the use of compounds ofFormula I for the treatment of altered motor function associated withdisorders of the gastro-intestinal and urinary tract.

A further aspect of the invention relates to the use of compounds ofFormula I for the treatment of pain associated with post-operativeileus.

Compounds of Formula I have utility in the prevention and treatment ofdisorders of the skin wholly or partially mediated by Group Imetabotropic glutamate receptors.

A further aspect of the invention relates to the use of compounds ofFormula I for the prevention and treatment of disorders of the skinwholly or partially mediated by Group I metabotropic glutamatereceptors.

The compounds of Formula I may be used in combination with one or moreother drugs in the treatment, prevention, control, amelioration, orreduction of risk of diseases or conditions for which compounds ofFormula I or the other drugs may have utility, where the combination ofthe drugs together are safer or more effective than either drug alone.Such other drug(s) may be administered, by a route and in an amountcommonly used therefor, contemporaneously or sequentially with one ormore compound of Formula I. When one or more compound of Formula I isused contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound(s) of Formula I is preferred. However, the combination therapymay also include therapies in which the compound(s) of Formula I and oneor more other drugs are administered on different overlapping schedules.It is also contemplated that when used in combination with one or moreother active ingredients, the compounds of Formula I and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to one or more compound of Formula I.

The above combinations include combinations of one or more compound ofFormula I not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of Formula I may beused in combination with other drugs that are used in the prevention,treatment, control, amelioration, or reduction of risk of the diseasesor conditions for which compounds of Formula I are useful. Such otherdrugs may be administered, by a route and in an amount commonly usedtherefor, contemporaneously or sequentially with one or more compound ofFormula I. When one or more compound of Formula I is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound(s)of Formula I is preferred. Accordingly, the pharmaceutical compositionsof Formula I include those that also contain one or more other activeingredients, in addition to one or more compound of Formula I.

Drugs suitable for combination with compounds of Formula 1 are wellknown to those with skill in the art, and can be identified byinspection of, inter alia, in Physician's Desk Reference (MedicalEconomics Company, Montvale, N.J.) and The Merck Index (Merck and Co.,Inc., Whitehouse Station, N.J.).

In one embodiment, the subject compound may be employed in combinationwith anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen,vitamin E, and anti-amyloid antibodies.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl(benzhexyl)hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.Lisuride and pramipexol are commonly used in a non-salt form.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexyl, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundmay be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as aminorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,.alpha.-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, agonists or antagonists,especially 5-HT_(1A) partial agonists, and corticotropin releasingfactor (CRF) antagonists. Specific agents include: amitriptyline,clomipramine, doxepin, imipramine and trimipramine; amoxapine,desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine,fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine,tranylcypromine and selegiline; moclobemide: venlafaxine; aprepitant;bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam,chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam,lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone andipsapirone, and pharmaceutically acceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

In still another embodiment, compounds of Formula I may be employed incombination with anticancer agents including, but not limited tomitomycin C, cyclophosphamide, busulfan, ifosfamide, isosfamide,5′-deoxy-5-fluoro-N-pentyloxycarbonyl-cytidine, tamoxifen, melphalan,hexamethylmelamine, thiotepa, chlorambucil, methyl-CCNU, temozolomide,dibromodulcitol, methotrexate, trimextrate, aldesleukin,interferon-alpha-2b, interleukin-2, dacarbazine, gemcitabine,capecitabine, azacytidine, 5-fluorouracil, cytarabine, 2-fluorodeoxycytidine, piritrexim, methotrexate, idatrexate, tomudex, trimetrexate,doxorubicin, epirubicin, etoposide, teniposide, mitoxantrone,irinotecan, 7-ethyl-10-hydroxy-camptothecin, topotecan, paclitaxel,docetaxel, vinblastine, vincristine, vinorelbine, cisplatin,oxaliplatin, spiroplatinum, and carboplatinum.

The compounds of Formula I may be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, depot, or implant), byinhalation spray, nasal, vaginal, rectal, sublingual, or topical routesof administration and may be formulated, alone or together, in suitabledosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration. In addition to the treatment ofwarm-blooded animals such as mice, rats, horses, cattle, sheep, dogs,cats, monkeys, etc., the compounds of the invention are effective foruse in humans.

The pharmaceutical compositions for the administration of the compoundsof Formula I may conveniently be presented in dosage unit form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of Formula I may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agents.

The pharmaceutical compositions may be in the form of sterile injectableaqueous solutions, micellar formulations or oleaginous suspensions.Suspensions may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butane diol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables. The pharmaceutical compositions for use as sterileinjectable solutions may be colloidal compositions consisting ofpolymeric micelles which contain within compounds of Formula I (U.S.Pat. No. 6,338,859 to Leroux, J. et al 2000).

The compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of Formula I are employed. It is intendedthat topical application according to the present invention shallinclude mouth washes, dentifrices, and gargles.

In the treatment of conditions which require negative allostericmodulation of Group 1 metabotropic glutamate receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. Preferably, the dosage level will be about 0.1 to about250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.A suitable dosage level may be about 0.01 to 250 mg/kg per day, about0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within thisrange the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.For oral administration, the compositions are preferably provided in theform of tablets, capsules, caplets, or pills containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20,25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day. This dosage regimenmay be adjusted by healthcare providers with knowledge and skill in theart to provide the optimal therapeutic response. It will be understood,however, that the specific dose level and frequency of dosage for anyparticular patient may be varied and will depend upon a variety offactors including the activity of the specific compound employed, themetabolic stability and length of action of that compound, the age, bodyweight, general health, sex, diet, mode and time of administration, rateof excretion, drug combination, the severity of the particularcondition, and the host undergoing therapy.

Compounds of Formula 1 may be prepared by methods known to those ofskill in the art, or may be commercially available. Compound 1 (Table 1)is available from Sigma-Aldrich (St. Louis, Mo., Cat. No. N3510).Compound 6 (Cat. No. 250581) is also available from Aldrich. Compound 5is available from TCI America (Portland, Oreg., Cat. No. 10668). Thebenzamides may be synthesized by condensing the appropriate benzoic acidderivative with a chosen amine. Typically, a benzoic acid or benzoylchloride derivative is reacted with the appropriate amine in a solventfor a specified time at a specified temperature, and the product amineis isolated and optionally purified. Some compounds of Formula 1 havebeen disclosed, although the inventors could find no reference to prioruse of compounds of Formula 1 used to treat disorders and diseasesmoderated by Group 1 mGluRs. For example, compound 1 (Table 1) is awell-known pharmaceutical substance, and compound 5 is a well-knownbactericide. Compound 3 is disclosed in WO 2004041256; compound 10 isdisclosed in WO 2005007151; compounds 6, 13, 14, 17, 19, and 20 aredisclosed in US Pre-grant Publication 2005018700; and compound 21 isdescribed in Schraufstatter, E. et al 1961; Zeitschr. fuer Naturfor.16b:95-108.

EXAMPLES

For the purposes of clarification of the 1H NMR spectral data, thedesignations in Formula II are followed.

Example 1 N-(2-chloro-4-nitrophenyl)-2 hydroxybenzamide (Compound 4)

The method disclosed in U.S. Pat. No. 3,079,297 to Shraufstatter et alwith minor variations was utilized. A boiling solution of salicylic acid(1.03 g, 7.46 mmol) and 2-chloro-4-nitroaniline (1.29 g, 7.46 mmol) inxylenes (20 mL) was treated dropwise with a solution of phosphoroustrichloride in dichloromethane 2.0M, 1.50 mL, 0.40 equiv.), and theresulting solution was refluxed (137° C.) for four hours. The solutionwas cooled to about 125° C. An oily residue covered the bottom and sidesof the reaction vessel. The hot reaction solution was transferred byglass pipette to a beaker and was allowed to cool to room temperaturewhile being stirred rapidly. The product separated, was collected byfiltration, and washed with hexanes, then recrystallized from ethanol.The title compound was obtained, MP 218-220° C. (dec.). ¹HNMR (500 MHz,DMSO-d₆): δ 7.02 (m, 1H, H3), 7.07 (m, 1H, H5), 7.49 (m, 1H, H4), 8.04(m, 1H, H6), 8.28 (m, 1H, H5′), 8.41 (m, 1H, H3′), 8.85 (m, 1H, H6′),11.8 (s, 1H, NH), 12.34 (s, 1H, OH).

Example 2 3,5-dichoro-N-(2-chloro-4-nitrophenyl)-2 hydroxybenzamide(Compound 2)

This material was prepared according to the method of Example 1 using3,5-dichlorosalicylic acid and 2-chloro-4-nitroaniline, with reagentsand solvents employed in similar molar ratios. ¹HNMR (500 MHz, DMSO-d₆):δ 7.85 (m, 1H, H4), 7.98 (m, 1H, H5), 8.29 (m, 1H, H5′), 8.04 (m, 1H,H6), 8.44 (m, 1H, H3′), 8.55 (m, 1H, H6′).

Example 3 2-Hydroxy-4-chloro-N-4-nitrophenylbenzamide (Compound 7)

This material was prepared according to the method of Example 1 using5-chlorosalicylic acid and 4-nitroaniline, with reagents and solventsemployed in similar molar ratios. ¹HNMR (500 MHz, DMSO-d₆): δ 7.04 (m,1H, H3), 7.48 (m, 1H, H4), 7.84 (m, 1H, H6), 7.99 (m, 2H, H2′ and H6′),8.27 (m, 2H, H3′ and H5′).

Example 4 5-Chloro-2-hydroxy-N-(3-vinylphenyl)benzamide (Compound 11)

This material was prepared according to the method of Example 1 using5-chlorosalicylic acid and 3-vinylaniline, with reagents and solventsemployed in similar molar ratios. ¹HNMR (500 MHz, DMSO-d₆): δ 5.32 (m,1H, C═CH₂ cis), 5.83 (m, 1H, C═CH₂trans), 6.75 (m, 1H, ArCH═CH₂), 7.02(m, 1H, H3), 7.28 (m, 1H, H6′), 7.37 (m, 1H, H5′), 7.49 (m, 1H, H4),7.62 (m, 1H, H4′), 7.80 (m, 1H, H2′), 7.90 (m, 1H, H6).

Example 5 5-Chloro-2-hydroxy-N-(3-ethylphenyl)benzamide (Compound 12)

This material was prepared according to the method of Example 1 using5-chlorosalicylic acid and 3-ethylaniline, with reagents and solventsemployed in similar molar ratios. ¹HNMR (500 MHz, DMSO-d₆): δ 1.20 (t,3H), 2.62 (q, 1H), 7.02 (m, 2H), 7.28 (m, 1H), 7.47 (m, 1H), 7.54 (m,1H), 7.56 (br s, 1H), 7.90 (m, 1H), 10.34 (s, 1H).

Example 6 5-Chloro-2-hydroxy-N-(3-methoxyphenyl)benzamide (Compound 15)

This material was prepared according to the method of Example 1 using5-chlorosalicylic acid and m-anisidine, with reagents and solventsemployed in similar molar ratios. ¹HNMR (500 MHz, DMSO-d₆): δ 3.72 (s,3H), 6.74 (m, 1H), 7.09 (m, 1H), 7.26 (br m, 2H), 7.40 (br s, 1H), 7.47(m, 1H), 7.88 (m, 1H), 10.34 (s, 1H).

Example 7 5-Chloro-N-(3-cyanophenyl)-2-hydroxybenzamide (Compound 16)

This material was prepared according to the method of Example 1 using5-chlorosalicylic acid and 3-aminobenzonitrile, with reagents andsolvents employed in similar molar ratios. ¹HNMR (500 MHz, DMSO-d₆): δ3.72 (s, 3H), 6.74 (m, 1H), 7.05 (m, 1H), 7.45 (m, 1H), 7.58 (br m, 2H),7.83 (m, 1H), 7.88 (m, 1H), 8.19 (br s, 1H), 10.59 (s, 1H).

Example 8 5-Chloro-N-(3-tert-butylphenyl)-2-hydroxybenzamide (Compound18)

This material was prepared according to the method of Example 1 using5-chlorosalicylic acid and 3-tert-butylaniline with reagents andsolvents employed in similar molar ratios. ¹HNMR (500 MHz, DMSO-d₆): δ1.28 (s, 9H), 7.00 (d, 1H), 7.18 (m, 1H), 7.24 (m, 1H), 7.46 (dd, 1H),7.56 (m, 1H), 7.68 (m, 1H), 7.95 (d, 1H), 10.38 (s, 1H), 11.90 (br s,1H).

Example 9 4-Chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl benzoate(Compound 22)

A suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide(1.27 g., 3.88 mmol) in pyridine (15 mL) was treated with4-dimethylaminopyridine (30 mg) and benzoyl chloride (0.49 mL, 4.27mmol) was introduced dropwise. The suspension was warmed to 50° C. forone hour then cooled to room temperature and stirred for 17 hours. Thereaction mixture was partitioned between 1N aqueous HCl and ethylacetate. The ethyl acetate phase was washed with water, then brine,dried over magnesium sulfate, and concentrated to an off-white solid.This was recrystallized from ethyl acetate/hexanes. ¹HNMR (500 MHz,DMSO-d₆): δ7.70 (M, 3H), 7.73 (m, 2H), 7.89 (m, 1H), 7.93 (M, 1H), 8.19(m, 1H), 8.32 (m, 1H), 10.60 (s, 1H).

Example 10 4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl dimethylcarbamate (Compound 23)

A suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide(238 mg, 0.728 mmol) in pyridine (5 mL) was treated with4-dimethylaminopyridine (5 mg) and dimethyl carbamoyl chloride (0.16 mL)was introduced dropwise. The resulting suspension was warmed to refluxfor three hours, then cooled to room temperature. 1N aqueous HCl (20 mL)was added, causing the product to crystallize. The crude product wascollected by filtration, dried under vacuum then recrystallized fromethyl acetate to give an off-white solid. ¹HNMR (500 MHz, DMSO-d₆): δ2.845 (s, 3H, N-methyl), 2.98s (s, 3H, N-methyl), 7.329 (d, J=9 Hz, 1H,H3), 7.641 (dd, J=3, 9 Hz, 1H, H4), 7.754 (d, J=3 Hz, 1H, H6), 8.079 (d,J=9 Hz, 1H, H6′), 8.264 (dd, J=3, 9 Hz, 1H, H5′), 8.392 (d, J=3 Hz),10.370 (s, 1H, OH).

Example 11 (R)-4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (Compound 24)

A suspension of (R)-(−)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic acid(Sigma-Aldrich, St. Louis, Mo.) (2.17 g, 12.46 mmol) in chloroform (24mL) was treated with oxalyl chloride (2.11 mL, 25 mmol) and a drop ofN,N-dimethylformamide was added. The progression of reaction wasmonitored by the observation of gas evolution by means of a bubbler.After 2 hours at room temperature, the reaction mixture was warmed to50° C. for 2 hours, cooled to room temperature, and concentrated toremove volatiles. This residue was diluted with chloroform (10 mL) andadded to a suspension of5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (2.04 g, 6.23mmol) in pyridine (30 mL) in which 4-dimethylaminopyride (20 mg) hadbeen previously dissolved. The reaction mixture was stirred at roomtemperature for 16 h and then was partitioned between 1N aqueous HCl andethyl acetate. The ethyl acetate solution was dried over magnesiumsulfate and concentrated to a dark oil. The residue was dissolved inchloroform and placed upon a short column of silica gel (60 mm i.d.×15mm). The product was eluted with chloroform and concentrated to an oil.The product was crystallized with a mixture of hexanes and ethylacetate. ¹HNMR (300 MHz, DMSO-d₆): δ 1.456 (s, 3H), 1.495 (s, 3H), 4.939(m, 1H), 7.352 (d, J=9 Hz, 1H, H3), 7.730 (dd, J=3.9 Hz, 1H, H4), 7.851(d, J=3 Hz, 1H, H6), 8.110 (d, J=9 Hz, 1H, H6′), 8.255 (dd, J=3, 9 Hz,1H, H5′), 8.411 (d, J=3 Hz, 1H, H3′), 10.481 (s, 1H, NH).

Example 12 (S)-1-(4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl2-methyl pyrrolidine-1,2-dicarboxylate (Compound 25)

(S)-Methyl 1-(chlorocarbonyl)pyrrolidine-2-carboxylate was preparedfollowing the procedure disclosed in U.S. Pat. No. 4,866,087 to Greenleeet al with minor modification. A solution of 5.63 g (19.0 mmol)bis(trichloromethyl carbonate in chloroform (15 mL) was added dropwiseto a solution of (S)-Methyl pyrrolidine-2-carboxylate hydrochloride(2.62 g., 15.82 mmol) and diisopropylethylamine (11.0 mL, 63.28 mmol) inchloroform (15 mL) at ice-bath temperature. After one hour, the solutionwas washed with 1 N aqueous HCl and water, and dried over magnesiumsulfate. The dried solution was concentrated and placed on a 85 mmi.d.×35 mm column of silica gel. The product was eluted in 20 percentethyl acetate in hexanes and concentrated to a colorless oil. This wasdissolved in chloroform (10 mL) and added to a suspension of5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (645 mg, 1.97mmol) in pyridine (15 mL) containing 20 mg of 4-dimethylaminopyridine.After stirring for 120 hours at room temperature, the reaction solutionwas partitioned between 1N aqueous HCl and ethyl acetate. The ethylacetate phase was washed with water, then brine, and dried overmagnesium sulfate. Concentration afforded an off-white solid which wasrecrystallized from ethyl acetate/hexanes. The ¹H NMR spectrum iscomplex and reveals the existence of rotational isomers due torestricted rotation about the pyrrolidine-1-carboxylate bond. ¹HNMR (300MHz, DMSO-d₆): δ 1.823-2.003 (m, 3H, pyrrolidine C4 methylene andpyrrolidine C3 syn-H), 2.213 (m, 1H, pyrrolidine C3 anti-H), 3.450 (m,1H, pyrrolidine C5), 3.599 (m, 1H, pyrrolidine C5), 3.600 (s, 1.5H,methyl ester), 3.621 (s, 1.5H, methyl ester), 4.252 (m, 0.5H,pyrrolidine methine), 4.541 (m, 0.5H, pyrrolidine methine), 7.108 (d,J=8.5 Hz, 0.33H, H3), 7.216 (d, J=8.5 Hz, 0.33H, H3), 7.361 (d, J=9 Hz,0.33H, H3), 7.545 (m, 0.33H, H4), 7.665 (m, 0.66H, H4), 7.763 (m, 0.66H,H6), 7.974 (m, 0.33H, H6), 8.133 (m, 0.66H, H6′), 8.287 (m, 1H, H5′),8.302 (m, 0.33H, H3′), 8.539 (m, 0.33H, H3′), 8.446 (m, 0.33H, H3′),8.822 (d, J=9.5 Hz, 0.33H, H6′), 10.313 (s, 0.33H, NH), 10.385 (s,0.33H, NH), 11.367 (br s, 0.17H, NH), 12.519 (br s, 0.17H, NH).

Example 13 (S)-2-tert-butyl1-(4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenylpyrrolidine-1,2-dicarboxylate (Compound 26)

(S)-tert-butyl 1-(chlorocarbonyl)pyrrolidine-2-carboxylate was preparedfollowing the procedure disclosed in U.S. Pat. No. 4,866,087 to Greenleeet al with minor modification. A solution of 1.06 g (6.19 mmol)(S)-2-tert-butyl pyrrolidine-2-carboxylate and diisopropylethylamine(3.2 mL, 18.57 mmol) in dichloromethane (5.0 mL) was introduced dropwiseinto a solution of 1.84 g (6.19 mmol) bis(trichloromethyl)carbonate indichloromethane (5.0 mL) at ice-bath temperature. The mixture wasallowed to warm to room temperature and was stirred for one hour. Thereaction mixture was washed with 1N aqueous HCl, dried over magnesiumsulfate, and concentrated to an oil. The residue was dissolved inchloroform (5.0 mL) and added dropwise to a suspension of5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (1.82 g, 5.57mmol) in pyridine (25 mL) containing 20 mg 4-dimethylaminopyridine. Thereaction mixture was stirred at room temperature for 72 hours, thenpartitioned between ethyl acetate and 1N aqueous HCl, dried overmagnesium sulfate, and concentrated to a solid. The product was isolatedusing silica gel chromatography with 3 ethyl acetate:7 hexanes aselution solvent. The product was recrystallized from ethylacetate/hexanes. ¹H NMR reveals the existence of approximately a 1:1ratio of rotational isomers. ¹H NMR (CDCl₃): δ1.331 (s, 4.5H, tert-butylester), 1.369 (s, 4.5H, tert-butyl ester), 1.833 (m, 3H, pyrrolidine C4methylene and pyrrolidine C3 syn-H), 2.181 (m, 1H, pyrrolidine C3anti-H), 3.500 (m, 2H, pyrrolidine C5 methylene), 4.113 (m, 0.5H,pyrrolidine methine), 4.362 (m, 0.5H, pyrrolidine methine), 7.158 (d,J=9 Hz, 0.5H, H3), 7.334 (d, J=9 Hz, 0.5H, H3), 7.661 (m, 1H, H4), 7.762(m, 1H, H6), 8.131 (m, 1H, H6′), 8.312 (m, 1H, H5′), 8.388 (m, 1H, H3′),10.274 (s, 0.5H, NH), 10.347 (s, 0.5H, NH).

Example 14(S)-1-((4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)carbonyl)pyrrolidine-2-carboxylicacid (Compound 27)

A solution of 269 mg (S)-2-tert-butyl1-(4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenylpyrrolidine-1,2-dicarboxylate in chloroform (4.0 mL) was treated withwater (0.2 mL) and trifluoroacetic acid (4.0 mL) was added. The reactionmixture was stirred at room temperature for 1.5 hours then concentrated.The residue was taken up in chloroform (15 mL) and concentrated. Theresidue was dissolved in ethyl acetate (10 mL) and concentrated toprovide a white solid. ¹H NMR reveals the existence of approximately a1:1 ratio of rotational isomers. ¹H NMR (CDCl₃): δ2.043 (m, 2H,pyrrolidine C4 methylene), 2.278 (m, 2H, pyrrolidine C3 methylene),3.685 (m, 2H, pyrrolidine c5 methylene), 4.414 (m, 0.5H, pyrrolidinemethine), 4.593 (m, 0.5H, pyrrolidine methine), 7.109 (d, J=9 Hz, 0.5H,H3), 7.201 (d, J=9 Hz, 0.5H, H3), 7.492 (m, 1H, H4), 7.841 (m, 1H, H6),8.196 (m, 1H, H6′), 8.299 (m, 1H, H5′), 8.760 (m, 1H, H3′), 8.852 (m,1H, NH).

Example 15

Cells stably transfected with mGlu1 or mGlu5 were grown 18 hours priorto the test in culture medium containing 600 ng/ml doxycycline, thenwere detached by gentle flushing with PBS-EDTA, recovered bycentrifugation and resuspended in “assay buffer” (HBSS, 2.1 mM CaCl2, 3μg/ml GPT (Glutamate-Pyruvate transaminase), 4 mM MEM Sodium Pyruvate,0.1% BSA, protease free). Cells were incubated at room temperature forat least 4 h with coelenterazine-h. Dose response curves were performedusing mGluR1 cells with the orthosteric agonist glutamate and negativeallosteric modulator JNJ16259685. Dose response curves were performedusing mGluR5 cells with the orthosteric agonist glutamate and negativeallosteric modulator MPEP. For agonist testing, 30 μl of cell suspensionwere mixed with 30 μl of test compound or reference agonist in a384-well plate. The resulting emission of light was recorded using theHamamatsu Functional Drug Screening System 6000 (FDSS 6000). Fornegative allosteric modulator testing, 60 μl of the resulting cellsuspension containing the test compound was mixed with 30 μl of thereference agonist at EC80 following an incubation of 3 min after thefirst injection. The resulting emission of light was recorded using FDSS6000. To standardize the emission of recorded light (determination ofthe “100% signal”) across plates and across different experiments, someof the wells contained 100 μM digitonin or a concentration of referenceagonist equivalent to the EC100. Plates also contained the referenceagonist at a concentration equivalent to the EC80 obtained during thetest validation. Negative allosteric modulator activity of test compoundwas expressed as a percentage of the stimulation of reference agonistactivity at its EC80 concentration.

Example 16

A total of 50, male Sprague-Dawley rats (125-150 g weight) were receivedfrom Ace Animals. Animals were housed in cages which conform to the sizerecommendations in the most recent NIH Guide for the Care and Use ofLaboratory Animals. The animal room was temperature controlled and had a12-hour light/dark cycle. The animals were fed Purina Rodent Chow #5012.The animals were acclimated to the facility for 7 days prior to thestudy. A pre-operative baseline paw withdrawal measure was collected forall rats. All rats underwent partial sciatic nerve ligation or a shamsurgery (allocated randomly), and had a three week recovery period.After recovery, a pre-dosing baseline paw withdrawal threshold wascollected for all rats. The results of this measure was used to assignrats to treatment groups in a stratified random fashion. Rats werelightly anesthetized and treated with test article or vehicle. Pawwithdrawal thresholds were determined at one, three, five, and 24 hourspost dosing. The sciatic nerve was partially ligated as a model ofneuropathic pain (Y. Shir & Z. Seltzer, 1990, Neurosci. Lett.,115:62-7). Briefly, under gas anesthesia, the skin and muscles of thethigh were reflected to expose the sciatic nerve. About one third to onehalf of the cross-sectional area of the nerve was tightly ligated usinga 7-0 nylon suture. The incision was closed in layers (suture formuscle, surgical adhesive for skin). Test article or vehicle wasadministered by transcutaneous injection (C. Mestre et al., 1994, J.Pharm. Tox. Meth., 32:197-200). Briefly, the rat was lightlyanesthetized and placed to flex the lower lumbar vertebrae. Afterpalpating the vertebral processes, a 26 gauge needle was insertedthrough a vertebral interspace. The presence of a tail flick wasconsidered validation of the needle placement; the solution was theninjected. Paw withdrawal thresholds were assessed using a paw pressuredevice (L. O. Randall & J. J. Selitto, 1957, Arch. Int. Pharmacodyn.,111:409-19). The behavioral endpoint was defined as paw withdrawal. Datawas analyzed by two-way analysis of variance (repeated measures) withBonferroni tests at individual time points. Paw withdrawal threshold rawvalues were used for the analysis, and each route of administration wasanalyzed separately. Vehicle-treated groups were used as the statisticalcomparison groups. All groups began the study with normal paw withdrawalthresholds (FIG. 1, Pre-Sx time point). Partial sciatic nerve ligation(PSN) surgery decreased withdrawal thresholds compared to sham (control)surgery. This hyperalgesia is characteristic of the model. Sham/vehicleand PSN/vehicle groups maintained relatively stable average thresholds,despite relatively small group sizes (PSN/vehicle, n=7; all othergroups, n=6). The differences between sham/vehicle and PSN/vehiclegroups were statistically significant at all post-surgery time points.Gabapentin was effective in reversing hyperalgesia. The reversal ofhyperalgesia seen with gabapentin is consistent with that seen aftertreatment with compounds known to have clinical activity againstneuropathic pain.

Each and every patent, published patent application, and other referencecited above is incorporated herein in its entirety.

Those with skill in the art will recognize, or be able to ascertainusing no more than routine experimentation, many equivalents to thespecific embodiments of the invention described herein. Such equivalentsare within the scope of the present invention and are intended to beencompassed by the following claims.

We claim:
 1. A method of treating pain by administering a noncompetitiveGroup 1 mGluR negative allosteric modulator compound, itspharmaceutically acceptable salts, prodrugs, or pharmaceuticallyacceptable salts of its prodrugs to an animal wherein said compound hasthe formula:


2. The method of claim 1 wherein said pain is acute or chronic pain. 3.The method of claim 1 wherein said pain is selected from the groupconsisting of bone and joint pain, repetitive motion pain, dental pain,cancer pain, myofacial pain, perioperative pain, chronic pain,neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraineand migraine headache, neuropathic pain, diabetic neuropathy, entrapmentneuropathy, phantom pain, thalamic pain after stroke, post-herpeticneuralgia, atypical facial neuralgia pain after tooth extraction, painfrom spinal cord injury, trigeminal neuralgia and cancer pain resistantto narcotic analgesics.
 4. The method of claim 1 wherein said pain isdiabetic neuropathy.
 5. The method of claim 1 wherein said pain isneuropathic pain.